The present invention provides novel compounds, novel compositions, method of their use and methods of their manufacture, such compounds generally useful pharmacologically as agents in those disease states alleviated by the alteration of mitogen activated signalling pathways in general, and in particular in the inhibition or antagonism of protein kinases, which pathologically involve aberrant cellular proliferation, such disease states including tumor growth, restenosis, atherosclerosis, and thrombosis. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful in protecting a patient undergoing chemotherapy from chemotherapy-induced alopecia.
Cell growth, differentiation, metabolism and function are extremely tightly controlled in higher eukaryotes. The ability of a cell to rapidly and appropriately respond to the array of external and internal signals it continually receives is of critical importance in maintaining a balance between these processes (Rozengurt, Current Opinion in Cell Biology 1992, 4, 161-5; Wilks, Progress in Growth Factor Research 1990, 2, 97-111). The loss of control over cellular regulation can often lead to aberrant cell function or death, often resulting in a disease state in the parent organism.
The protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function (Hanks, et al., Science 1988, 241, 42-52). A partial list of such kinases includes ab1, ATK , bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie1, tie2, TRK,Yes, and Zap70.
One of the most commonly studied pathways involving kinase regulation is cellular signalling from receptors at the cell surface to the nucleus (Crews and Erikson, Cell 1993, 74, 215-7) . One example of this pathway includes a cascade of kinases in which members of the Growth Factor receptor Tyrosine Kinases (such as EGF-R, PDGF-R, VEGF-R, IGF1-R, the Insulin receptor), deliver signals through phosphorylation to other kinases such as Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase families (Crews and Erikson, Cell 1993, 74, 2157; Ihle, et al., Trends in Biochemical Sciences 1994, 19, 222-7). Each of these kinases is represented by several family members (Pelech and Sanghera, Trends in Biochemical Sciences 1992, 17, 233-8) which play related, but functionally distinct roles. The loss of regulation of the growth factor signalling pathway is a frequent occurence in cancer as well as other disease states.
The signals mediated by kinases have also been shown to control growth, death and differentiation in the cell by regulating the processes of the cell cycle (Massague and Roberts, Current Opinion in Cell Biology 1995, 7, 769-72). Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs) (Myerson, et al., EMBO Journal 1992, 11, 2909-17). The regulation of CDK activation is complex, but requires the association of the CDK with a member of the cyclin family of regulatory subunits (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 275-80; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27). A further level of regulation occurs through both activating and inactivating phosphorylations of the CDK subunit (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 275-80; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27; Ducommun, et al., EMBO Journal 1991, 10, 3311-9; Gautier, et al., Nature 1989, 339, 626-9; Gould and Nurse, Nature 1989, 342, 3945; Krek and Nigg, EMBO Journal 1991, 10, 333141; Solomon, et al., Cell 1990, 63, 1013-24). The coordinate activation and inactivation of different cydin/CDK complexes is necessary for normal progression through the cell cycle (Pines, Trends in Biochemical Sciences 1993, 18, 195-7; Sherr, Cell 1993, 73, 1059-65). Both the critical G1-S and G2-M transitions are controlled by the activation of different cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclin E/CDK2 are thought to mediate the onset of S-phase (Matsushime, et al., Molecular and Cellular Biology 1994, 14, 2066-76; Ohtsubo and Roberts, Science 1993, 259, 1908-12; Quelle, et al., Genes and Development 1993, 7, 1559-71; Resnitzky, et al., Molecular and Cellular Biology 1994, 14, 1669-79). Progression through S-phase requires the activity of cyclin A/CDK2 (Girard, et al., Cell 1991, 67, 1169-79; Pagano, et al., EMBO Journal 1992, 11, 961-71; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824-8; Walker and Mailer, Nature 1991, 354, 314-7; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144-54) whereas the activation of cyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset of metaphase (Draetta, Trends in Cell Biology 1993, 3, 287-9; Murray and Kirschner, Nature 1989, 339, 27580; Solomon, et al., Molecular Biology of the Cell. 1992, 3, 13-27; Girard, et al., Cell 1991, 67, 1169-79; Pagano, et al., EMBO Journal 1992, 11, 961-71; Rosenblatt, et al., Proceedings of the National Academy of Science USA 1992, 89, 2824-8; Walker and Maller, Nature 1991, 354, 314-7; Zindy, et al., Biochemical and Biophysical Research Communications 1992, 182, 1144-54). It is not surprising, therefore, that the loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer. (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82). The selective inhibition of CDKs is therefore an object of the present invention.
The compounds of the present invention are additionally useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the areas of blood vessel proliferative disorders, fibrotic disorders, mesangial cell proliferative disorders and metabolic diseases. Blood vessel proliferative disorders include arthritis and restenosis. Fibrotic disorders include hepatic cirrhosis and atherosclerosis. Mesangial cell proliferative disorders include glomerulonephrifis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection and glomerulopathies. Metabolic disorders include psoriasis, diabetes mellitus, chronic wound healing, inflammation, neurodegenerative diseases, macular degeneration, and diabetic retinopathy.
Inhibitors of kinases involved in mediating or maintaining these disease states represent novel therapies for these disorders. Examples of such kinases include, but are not limited to: (1) inhibition of c-Src (Brickell, Critical Reviews in Oncogenesis 1992, 3, 401-46; Courtneidge, Seminars in Cancer Biology 1994, 5, 239-46), raf (Powis, Pharmacology and Therapeutics 1994, 62, 57-95) and the cyclin-dependent kinases (CDKs) 1, 2 and 4 in cancer (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees, Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell 1994, 79, 573-82), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger, et al., Proceedings of the National Academy of Science USA 1995, 92, 2258-62), (3) inhibition of CDK5 and GSK3 kinases in Alzheimers (Hosoi, et al., Journal of Biochemistry (Tokyo) 1995, 117, 741-9; Aplin, et al., Journal of Neurochemistry 1996, 67, 699-707), (4) inhibition of c-Src kinase in osteoporosis (Tanaka, et al., Nature 1996, 383, 528-31), (5) inhibition of GSK-3 kinase in type-2 diabetes (Borthwick, et al., Biochemical and Biophysical Research Communications 1995, 210, 738-45); (6) inhibition of the p38 kinase in inflammation (Badger, et al., The Journal of Pharmacology and Experimental Therapeutics 1996, 279, 1453-61); (7) inhibition of VEGF-R 1-3 and TIE-1 andxe2x80x942 kinases in diseases which involve angiogenesis (Shawver, et al., Drug Discovery Today 1997, 2, 50-63); (8) inhibition of UL97 kinase in viral infections (He, et al., Journal of Virology 1997, 71, 405-11); (9) inhibition of CSF-1R kinase in bone and hematopoefic diseases (Myers, et al., Bioorganic and Medicinal Chemistry Letters 1997, 7, 421-4), and (10) inhibition of Lck kinase in autoimmune diseases and transplant rejection (Myers, et al., Bioorganic and Medicinal Chemistry Letters 1997, 7, 417-20).
It is additionally possible that inhibitors of certain kinases may have utility in the treatment of diseases when the kinase is not misregulated, but is nonetheless essential for maintenance of the disease state. In this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases. For example, many viruses, such as human papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle (Vousden, FASEB Journal 1993, 7, 872-9). Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2, may disrupt the virus life cycle by preventing virus replication. This same principle may be used to protect normal cells of the body from toxicity of cycle-specific chemotherapeutic agents (Stone, et al., Cancer Research 1996, 56, 3199-202; Kohn, et al., Journal of Cellular Biochemistry 1994, 54, 440-52). Inhibition of CDKs 2 or 4 will prevent progression into the cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis. Furthermore, CDK2/cyclin E activity has also been shown to regulate NF-kB: Inhibition of CDK2 activity stimulates NF-kB-dependent gene expression, an event mediated through interactions with the p300 coactivator (Perkins, et al., Science 1997, 275, 523-7). NF-kB regulates genes involved in inflammatory responses, (such as hematopoietic growth factors chemokines and leukocyte adhesion molecules) (Baeuerie and Henkel, Annual Review of Immunology 1994, 12, 141-79) and may be involved in the suppression of apoptotic signals within the cell (Beg and Baltimore, Science 1996, 274, 782-4; Wang, et al., Science 1996, 274, 784-7; Van Antwerp, et al., Science 1996, 274, 787-9). Thus, inhibition of CDK2 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF-kB. This therefore suggests that inhibition of CDK2 activity may also have utility in other cases where regulation of NF-kB plays a role in etiology of disease. A further example may be taken from fungal infections: Aspergillosis is a common infection in immune-compromised patients (Armstrong, Clinical Infectious Diseases 1993, 16, 1-7). Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A (Osmani, et al., EMBO Journal 1991, 10, 2669-79; Osmani, et al., Cell 1991, 67, 283-91) may cause arrest or death in the fungi, improving the therapeutic outcome for patients with these infections.
In brief summary, the invention comprises compounds of the formula (I): 
wherein
X is N, CH, CCF3, or C(C1-12 aliphatic);
R1 is hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Hetxe2x80x94C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-12 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Hetxe2x80x94C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C1-12 aliphatic-sulfonyl, aminosulfonyl, or C1-12 aliphatic-aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-12 aliphatic, halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy or oxo;
R3 is hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2, and R3 cannot simultaneously be H;
R4 is sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl -C-1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl, aminoiminoamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het below, or any of said used rings optionally substituted by C1-12 aliphatic, oxo or dioxo;
R6 is C1-12 aliphatic, hydroxy, C1-12 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Hetxe2x80x94C1-12-aliphatic, Hetxe2x80x94C1-12-alkoxy, di-Hetxe2x80x94C1-12-alkoxy Aryl, Aryl-C1-12 -aliphatic, Aryl-C1-12 -alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy or halo-C1-12 aliphatic;
Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;
Cyc is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, isoquinoline, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, quinoline, tetrahydrofuran, tetrazine, thidiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole, with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A more preferred genus of compounds of the present invention includes compounds of formula (I), defined as follows: 
wherein
X is N, CH, or C(C1-6 aliphatic);
R1 is hydrogen, C1-6 aliphatic, hydroxy-C1-6 aliphatic, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Hetxe2x80x94C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxycarbonyl, halogen, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-6 aliphatic, R7xe2x80x94C1-6 aliphatic, C1-6alkoxy, hydroxy-C1-6 aliphatic, C1-6 alkoxycarbonyl, carboxyl C1-6 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-6 aliphatic-aminocarbonyl, Aryl-C1-6 aliphatic-aminocarbonyl, R6-Aryl-C1-6 aliphatic-aminocarbonyl, Hetxe2x80x94C1-6 aliphatic-aminocarbonyl, hydroxy-C1-6 aliphatic-aminocarbonyl, C1-6alkoxy-C1-6 aliphatic-aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic-amino, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, halogen, hydroxy, nitro, sulfo, C1-6 aliphatic-sulfonyl, aminosulfonyl, C1-6 aliphatic-aminosulfonyl, or quaternary ammonium, where R7, Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het above, or any of said fused rings optionally substituted by halogen or oxo;
R3 is hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, C1-6 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het above, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is sulfonic acid, C1-12 aliphatic-sulfonyl, sulfonyl-C1-12 aliphatic, C1-12 aliphatic-sulfonyl-C1-6 aliphatic, C1-6 aliphatic-amino, R7-sulfonyl, R7-sulfonyl-C1-12 aliphatic, R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Arylamino, (R8)1-3-Arylsulfonyl, (R8)1-3-Aryl-aminosulfonyl, (R8)1-3-Aryl-sulfonylamino, Het-amino, Het-sulfonyl, Het-aminosulfonyl aminoiminoamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het above, or any of said used rings optionally substituted by oxo or dioxo;
R6 is hydrogen, C1-6 aliphatic, hydroxy, C1-6 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Hetxe2x80x94C1-12-aliphatic, Hetxe2x80x94C1-12-alkoxy, di-Hetxe2x80x94C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic,or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen or halo-C1-6 aliphatic;
Aryl is phenyl, or naphthyl;
Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone; and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A highly preferred genus of compounds of the present invention includes compounds of formula (I), defined as follows: 
wherein
X is N, CH, or CCH3;
R1 is hydrogen, C1-6 aliphatic, hydroxy-C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, Aryl-C1-6 aliphatic, R6-Aryl-C1-6 aliphatic, Cyc-C1-6 aliphatic, Hetxe2x80x94C1-6 aliphatic, C1-6 alkoxy, Aryloxy, aminocarbonyl, C1-6 alkoxycarbonyl, halogen, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-6 aliphatic, N-hydroxyimino-C1-6 aliphatic, C1-6alkoxy, C1-6 alkoxycarbonyl, Aryl, R6-Aryloxycarbonyl, Het, aminocarbonyl, C1-6 aliphatic aminocarbonyl, Aryl-C1-6 aliphatic aminocarbonyl, R6-Aryl-C1-6 aliphatic aminocarbonyl, Hetxe2x80x94C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, hydroxy-C1-6 aliphatic aminocarbonyl, C1-6-alkoxy-C1-6 aliphatic aminocarbonyl, C1-6 alkoxy-C1-6 aliphatic amino, halogen, hydroxy, nitro, C1-6 aliphatic sulfonyl, or aminosulfonyl, C1-6 aliphatic aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by halogen or oxo;
R3 is hydrogen, C1-6 aliphatic, hydroxy, hydroxy C1-6 aliphatic, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl C1-6 alkoxy, Aryloxy, Het, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 alkyl or C1-6 alkylcarbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is R7-sulfonyl, R7-sulfonyl C1-6-aliphatic, C1-6 aliphatic sulfonyl-C1-6 aliphatic, R7-aminosulfonyl, di-C1-6 aliphatic amino, di-C1-6 aliphatic aminocarbonyl, di-C1-6 aliphatic aminosulfonyl, di-C1-6 aliphatic aminosulfonyl-C1-6 aliphatic, R7-aminosulfonyl C1-6 aliphatic, aminosulfonylamino, R7xe2x80x94C1-6 aliphatic aminosulfonyl-C1-6 aliphatic, Aryl, Het, R8-Aryl-aminosulfonyl, Het-aminosulfonyl, or aminoiminoaminosulfonyl, where R7, R8, Aryl and Het are as defined below;
R5 is hydrogen;
and further wherein R4 and R5 are optionally joined to form a fused ring, said ring selected from the group as defined for Het below, or any of said used rings optionally substituted by oxo or dioxo;
R6 is hydroxy, C1-6 alkoxy, or halogen;
R7 is hydrogen, C1-6 aliphatic, hydroxy C1-6-alkoxy, hydroxy-C1-6 aliphatic, C1-6 aliphatic carbonyl, Aryl-carbonyl, C1-12 alkoxyalkoxyalkoxyalkoxyalkyl, hydroxyl, Aryl, Aryl-C1-6-alkoxy, Aryl-C1 6-aliphatic, Het, Hetxe2x80x94C1l6-alkoxy, di-Hetxe2x80x94C1-6 alkoxy, Hetxe2x80x94C1-6-aliphatic, di-Hetxe2x80x94C1-6-aliphatic;
R8 is trifluoromethyl;
Aryl is phenyl;
Cyc is cyclobutyl;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxolane, furan, imidazole, morpholine, oxazole, pyridine, pyrrole, pyrrolidine, thiadiazole, thiazole, thiophene, and triazole, with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates, solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
A preferred group of compounds of the present invention with respect to the substitutions at R4 are compounds of formula (I): 
wherein
X is NH;
R1 is hydrogen, C1-12 aliphatic, thiol, hydroxy, hydroxy-C1-12 aliphatic, Aryl, Aryl-C1-12 aliphatic, R6-Aryl-C1-12 aliphatic, Cyc, Cyc-C1-6 aliphatic, Het, Hetxe2x80x94C1-12 aliphatic, C1-12 alkoxy, Aryloxy, amino, C1-12 aliphatic amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyi, C1-12 alkoxycarbonyl, halogen, cyano, sulfonamide, or nitro, where R6, Aryl, Cyc and Het are as defined below;
R2 is hydrogen, C1-12 aliphatic, N-hydroxyimino-C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 aliphatic, C1-12 alkoxycarbonyl, carboxyl C1-12 aliphatic, Aryl, R6-Aryl-oxycarbonyl, R6-oxycarbonyl-Aryl, Het, aminocarbonyl, C1-12 aliphatic-aminocarbonyl, Aryl-C1-12 aliphatic-aminocarbonyl, R6-Aryl-C1-12 aliphatic-aminocarbonyl, Hetxe2x80x94C1-12 aliphatic-aminocarbonyl, hydroxy-C1-12 aliphatic-aminocarbonyl, C1-12-alkoxy-C1-12 aliphatic-aminocarbonyl, C1-12 alkoxy-C1-12 aliphatic-amino, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, halogen, hydroxy, nitro, C1-12 aliphatic-sulfonyl, aminosulfonyl, or C1-12 aliphatic-aminosulfonyl, where Aryl and Het are as defined below;
further wherein R1 and R2 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by halogen, nitro, cyano, C1-12 alkoxy, carbonyl-C1-12 alkoxy or oxo;
R3 is hydrogen, C1-12 aliphatic, hydroxy, hydroxy C1-12 aliphatic, di-C1-12 aliphatic amino, di-C1-12 aliphatic aminocarbonyl, di-C1-12 aliphatic aminosulfonyl, C1-12 alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below;
further wherein R2 and R3 are optionally joined to form a fused ring, said fused ring selected from the group as defined for Het below, or any of said fused rings optionally substituted by C1-6 aliphatic or C1-6 aliphatic-carbonyl;
with the proviso that R1, R2 and R3 cannot simultaneously be H;
R4 is R7-aminosulfonyl, R7-aminosulfonyl-C1-12 aliphatic, R7-sulfonylamino, R7-sulfonylamino-C1-12 aliphatic, aminosulfonylamino, di-C1-12 aliphatic aminosulfonyl, di-C1-12 aliphatic aminosulfonyl-C1-12 aliphatic, (R8)1-3-Aryl-aminosulfonyl,
(R8)1-3-Aryl-sulfonylamino, or aminoiminoaminosulfonyl, where R7, R8, Aryl and
Het are as defined below;
R5 is hydrogen;
R6 is C1-12 aliphatic, hydroxy, C1-12 alkoxy, or halogen;
R7 is hydrogen, C1-12 aliphatic, C1-12 alkoxy, hydroxy-C1-12 alkoxy, hydroxy-C1-12 aliphatic, carboxylic acid, C1-12 aliphatic-carbonyl, Het, Hetxe2x80x94C1-12-aliphatic, Hetxe2x80x94C1-12-alkoxy, di-Hetxe2x80x94C1-12-alkoxy Aryl, Aryl-C1-12-aliphatic, Aryl-C1-12-alkoxy, Aryl-carbonyl, C1-18 alkoxyalkoxyalkoxyalkoxyaliphatic, or hydroxyl where Het and Aryl are as defined below;
R8 is hydrogen, nitro, cyano, C1-12 alkoxy, halo, carbonyl-C1-12 alkoxy or halo-C1-12 aliphatic;
Aryl is phenyl, naphthyl, phenanthryl or anthracenyl;
Cyc is cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any one of which may have one or more degrees of unsaturation;
Het is a saturated or unsaturated heteroatom ring system selected from the group consisting of benzimidazole, dihydrothiophene, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, morpholine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, piperazine, piperadine, pyran, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, tetrahydrofuran, tetrazine, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thiophene, thiopyran, triazine and triazole with the proviso that when R2 is thiadiazine, then R4 cannot be methylsulfone;
and the pharmaceutically acceptable salts, biohydrolyzable esters, biohydrolyzable amides, biohydrolyzable carbamates solvates, hydrates, affinity reagents or prodrugs thereof in either crystalline or amorphous form.
Due to the presence of an oxindole exocyclic double bond, also included in the compounds of the invention are their respective pure E and Z geometric isomers as well as mixtures of E and Z isomers. The invention as described and claimed does not set any limiting ratios on prevalence of Z to E isomers. Thus compound number 104 in the tables below is disclosed and claimed as the E geometric thereof, the Z geometric isomer thereof and a mixture of the E and Z geometric isomers thereof, but not limited by any given ratio(s).
Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula.
Certain of the compounds as described will contain one or more chiral, or asymmetric, centers and will therefore be capable of existing as optical isomers that are either dextrorotatory or levorotatory. Also included in the compounds of the invention are the respective dextrorotatory or levorotatory pure preparations, and mixtures thereof.
Certain compounds of formula (I) above may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
The present invention also provides compounds of formula (I) and pharmaceutically acceptable salts thereof (hereafter identified as the xe2x80x98active compoundsxe2x80x99) for use in medical therapy, and particularly in the treatment of disorders mediated by CDK2 activity, such as alopecia induced by cancer chemotherapy.
A further aspect of the invention provides a method of treatment of the human or animal body suffering from a disorder mediated by a mitogen activated protein kinase which comprises administering an effective amount of an active compound of formula (I) to the human or animal patient.
Another aspect of the present invention provides the use of an active compound of formula (I), in the preparation of a medicament for the treatment of malignant tumors, or for the treatment of alopecia induced by cancer chemotherapy or induced by radiation therapy. Alternatively, compounds of formula (I) can be used in the preparation of a medicament for the treatment of a disease mediated by a kinase selected from the group consisting of ab1, ATK, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK4, CDK6, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, ERK, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie1, tie2, TRK, Yes, and Zap70. Additionally, compounds of formula (I) can be used in the preparation of a medicament for the treatment of organ transplant rejection, of inhibiting tumor growth, of treating chemotherapy-induced alopecia, chemotherapy-induced thrombocytopenia or chemotherapy-induced leukopenia, or of treating a disease state selected from the group consisting of mucocitis, restenosis, atherosclerosis, rheumatoid arthritis, angiogenesis, hepatic cirrhosis, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy, a glomerulopathy, psoriasis, diabetes mellitus, inflammation, a neurodegenerative disease, macular degeneration, actinic keratosis and hyperproliferative disorders.
Another aspect of the present invention provides the use of an active compound of formula (I), in coadministration with previously known anti-tumor therapies for more effective treatment of such tumors.
Another aspect of the present invention provides the use of an active compound of formula (I) in the preparation of a medicament for the treatment of viral or eukaryotic infections.
Other aspects of the present invention related to the inhibition of mitogen activated protein kinases are discussed in more detail below.
Compounds we have synthesized as part of the present invention which are currently preferred are listed in Tables 1 and 2 below. Compounds are identified by the numbers shown in the first column; variables below in the rest of the columns are with reference to the generic structure (I). Corresponding IUPAC nomenclature are disclosed in Table 2. Since all substituents at each point of substitution are capable of independent synthesis of each other, the tables are to be read as a matrix in which any combination of substituents is within the scope of the disclosure and claims of the invention.
For the sake of clarity, Examples 2 and 53 do not appear in Tables 1 and 2.
Standard accepted nomenclature corresponding to the Examples set forth in this specification are set forth below. In some cases nomenclature is given for one or more possible isomers.
The invention discloses six different points of substitution on structural formula (I). Each of these points of substitution bears a substituent whose selection and synthesis as part of this invention was independent of all other points of substitution on formula (I). Thus, each point of substitution is now further described individually.
Preferred substitutions at the R1 position include hydrogen, halogen, amide, nitro, lower alkyl, hydroxy, hydroxyalkyl, pyrimidineloweralkyl, loweralkoxycarbonyl, cyclic loweralkyl, hydroxyphenylloweralkyl, phenoxy, alkoxy, or pyrazole, or are fused with R2 to form fused thiazole, pyrazole, triazole, halogen-substituted diazole, acyl substituted pyrrole, and pyridine, rings. Most preferred are hydrogen, methyl and fused with R2 for form fused thiazole and fused pyridine. Most highly preferred are to be fused with R2 to form fused thiazole.
Preferred substitutions at the R2 position include hydrogen, halogen, sulfate, amine, quaternary amine, amide, ester, phenyl, alkoxy, aminosulfonyl, lower alkyl sulfonyl, furanyl lower alkyl amide, pyridinyl lower alkyl amide, alkoxy-substituted phenyl lower alkyl amide, morpholino lower alkyl amide, imidazolyl lower alkyl amide, hydroxy lower alkyl amide, alkoxy lower alkyl amide, lower alkyl amide, lower alkyl sulfonamide,lower alkyl hydroxy substituted amino, nitro, halogen-substituted phenoxycarbonyl, or triazole or oxazole rings, or are fused with R3 to form a fused oxazole, pyrrole, or dioxolane ring, which fused rings can be substituted by lower alkyl, lower alkyl carbonyl, or, when said fused ring is a hetero ring having nitrogen as the heteroatom, forming a quaternary ammonium salt ionically bonded with a halogen atom. Most preferred are hydrogen, hydroxyl, oxazolyl, or fused with R1 to form fused thiazolyl or fused pyridyl. Most highly preferred are to be fused with R1 to form fused thiazole.
Preferred substitutions at R3include hydrogen, lower alkyl, hydroxy lower alkyl, halogen, phenoxy, and alkoxy. Most preferred are hydrogen and methyl. Most highly preferred is hydrogen.
Preferred substitutions at R4 include sulfonylamino, sulfonylaminoamino, lower alkyl sulfonylamino, lower alkylsulfonyl lower alkyl, alkoxysulfonylamino, phenylcarbonylsulfonylamino, phenoxysulfonyl, hydroxy lower alkylsulfonylamino, hydroxy lower alkylsulfonylamino lower alkyl, alkyl, phenylsulfonylamino, optionally substituted by halogen substituted lower alkyl, aminoiminosulfonylamino, alkylsulfonylaminoalkyl, pyridinyl lower alkyl sulfonylamino, benzamideazolesulfonylamino, pyridyisulfonylamino, pyrimidinylsulfonylamino, thiadiazolylsulfonylamino optionally substituted by lower alkyl, thiazolesulfonylamino, hydroxyalkoxyalkylsulfonylamino, or the group 4xe2x80x2-SO2NH[(CH2)2O]4CH3, or are fused with R5 to form a fused imidazole, triazole, cyclic sulfonylamino or thiaphene ring optionally disubstituted on the sulfur heteroatom by oxo. The most preferred substitutions are 2 pyridine sulfonylamino, 4 pyridine sulfonylamino, hydroxy n-butyl sulfonylamino, methylsulfonylaminomethylene, sulfonyldimethylamino, fused 1,2,3-triazole, and sulfonylamino. Most highly preferred is 2 pyridine sulfonylamino, 4 pyridine sulfonylamino and hydroxy n-butyl sulfonylamino.
The preferred substitution at R5 is hydrogen.
Preferred substitutions at X include N, CH, and CCH3. Most preferred is NH.
Preferred individual compounds of the present invention include any one of the following compounds: 
Highly preferred compounds include 